Circulating gluten-specific FOXP3⁺CD39⁺ regulatory T cells have impaired suppressive function in patients with celiac disease

Background Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood. Objective We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3)+ Treg cells. Methods Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4+ T-cell response, we paired traditional IFN-γ ELISpot with an assay to detect antigen-specific CD4+ T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation but rather on antigen-induced coexpression of CD25 and OX40 (CD134). Results Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 80% of the ex vivo circulating gluten-specific CD4+ T cells were FOXP3+CD39+ Treg cells, which reside within the pool of memory CD4+CD25+CD127lowCD45RO+ Treg cells. Although we observed normal suppressive function in peripheral polyclonal Treg cells from patients with celiac disease, after a short in vitro expansion, the gluten-specific FOXP3+CD39+ Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells. Conclusion This study provides the first estimation of FOXP3+CD39+ Treg cell frequency within circulating gluten-specific CD4+ T cells after oral gluten challenge of patients with celiac disease. FOXP3+CD39+ Treg cells comprised a major proportion of all circulating gluten-specific CD4+ T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key contributor to disease pathogenesis

Arabidopsis MKS1 Is Involved in Basal Immunity and Requires an Intact N-terminal Domain for Proper Function

Innate immune signaling pathways in animals and plants are regulated by mitogen-activated protein kinase (MAPK) cascades. MAP kinase 4 (MPK4) functions downstream of innate immune receptors via a nuclear substrate MKS1 to regulate the activity of the WRKY33 transcription factor, which in turn controls the production of anti-microbial phytoalexins.We investigate the role of MKS1 in basal resistance and the importance of its N- and C-terminal domains for MKS1 function. We used the information that mks1 loss-of-function partially suppresses the mpk4 loss-of-function phenotype, and that transgenic expression of functional MKS1 in mpk4/mks1 double mutants reverted the mpk4 dwarf phenotype. Transformation of mks1/mpk4 with mutant versions of MKS1 constructs showed that a single amino acid substitution in a putative MAP kinase docking domain, MKS1-L32A, or a truncated MKS1 version unable to interact with WRKY33, were deficient in reverting the double mutant to the mpk4 phenotype. These results demonstrate functional requirement in MKS1 for the interaction with MPK4 and WRKY33. In addition, nuclear localization of MKS1 was shown to depend on an intact N-terminal domain. Furthermore, loss-of-function mks1 mutants exhibited increased susceptibility to strains of Pseudomonas syringae and Hyaloperonospora arabidopsidis, indicating that MKS1 plays a role in basal defense responses.Taken together, our results indicate that MKS1 function and subcellular location requires an intact N-terminus important for both MPK4 and WRKY33 interactions

Sunscreens - Which and what for?

It is well established that sun exposure is the main cause for the development of skin cancer. Chronic continuous UV radiation is believed to induce malignant melanoma, whereas intermittent high-dose UV exposure contributes to the occurrence of actinic keratosis as precursor lesions of squamous cell carcinoma as well as basal cell carcinoma. Not only photocarcinogenesis but also the mechanisms of photoaging have recently become apparent. In this respect the use of sunscreens seemed to prove to be more and more important and popular within the last decades. However, there is still inconsistency about the usefulness of sunscreens. Several studies show that inadequate use and incomplete UV spectrum efficacy may compromise protection more than previously expected. The sunscreen market is crowded by numerous products. Inorganic sunscreens such as zinc oxide and titanium oxide have a wide spectral range of activity compared to most of the organic sunscreen products. It is not uncommon for organic sunscreens to cause photocontact allergy, but their cosmetic acceptability is still superior to the one given by inorganic sunscreens. Recently, modern galenic approaches such as micronization and encapsulation allow the development of high-quality inorganic sunscreens. The potential systemic toxicity of organic sunscreens has lately primarily been discussed controversially in public, and several studies show contradictory results. Although a matter of debate, at present the sun protection factor (SPF) is the most reliable information for the consumer as a measure of sunscreen filter efficacy. In this context additional tests have been introduced for the evaluation of not only the protective effect against erythema but also protection against UV-induced immunological and mutational effects. Recently, combinations of UV filters with agents active in DNA repair have been introduced in order to improve photoprotection. This article reviews the efficacy of sunscreens in the prevention of epithelial and nonepithelial skin cancer, the effect on immunosuppression and the value of the SPF as well as new developments on the sunscreen market. Copyright (C) 2005 S. Karger AG, Basel

Statistical regularities in the rank-citation profile of scientists

Recent science of science research shows that scientific impact measures for journals and individual articles have quantifiable regularities across both time and discipline. However, little is known about the scientific impact distribution at the scale of an individual scientist. We analyze the aggregate production and impact using the rank-citation profile ci(r) of 200 distinguished professors and 100 assistant professors. For the entire range of paper rank r, we fit each ci(r) to a common distribution function. Since two scientists with equivalent Hirsch h-index can have significantly different ci(r) profiles, our results demonstrate the utility of the βi scaling parameter in conjunction with hi for quantifying individual publication impact. We show that the total number of citations Ci tallied from a scientist's Ni papers scales as . Such statistical regularities in the input-output patterns of scientists can be used as benchmarks for theoretical models of career progress

The Role of Innate APOBEC3G and Adaptive AID Immune Responses in HLA-HIV/SIV Immunized SHIV Infected Macaques

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The science of clinical practice: disease diagnosis or patient prognosis? Evidence about "what is likely to happen" should shape clinical practice.

BACKGROUND: Diagnosis is the traditional basis for decision-making in clinical practice. Evidence is often lacking about future benefits and harms of these decisions for patients diagnosed with and without disease. We propose that a model of clinical practice focused on patient prognosis and predicting the likelihood of future outcomes may be more useful. DISCUSSION: Disease diagnosis can provide crucial information for clinical decisions that influence outcome in serious acute illness. However, the central role of diagnosis in clinical practice is challenged by evidence that it does not always benefit patients and that factors other than disease are important in determining patient outcome. The concept of disease as a dichotomous 'yes' or 'no' is challenged by the frequent use of diagnostic indicators with continuous distributions, such as blood sugar, which are better understood as contributing information about the probability of a patient's future outcome. Moreover, many illnesses, such as chronic fatigue, cannot usefully be labelled from a disease-diagnosis perspective. In such cases, a prognostic model provides an alternative framework for clinical practice that extends beyond disease and diagnosis and incorporates a wide range of information to predict future patient outcomes and to guide decisions to improve them. Such information embraces non-disease factors and genetic and other biomarkers which influence outcome. SUMMARY: Patient prognosis can provide the framework for modern clinical practice to integrate information from the expanding biological, social, and clinical database for more effective and efficient care

Ears of the Armadillo: Global Health Research and Neglected Diseases in Texas

Neglected tropical diseases (NTDs) have\ud been recently identified as significant public\ud health problems in Texas and elsewhere in\ud the American South. A one-day forum on the\ud landscape of research and development and\ud the hidden burden of NTDs in Texas\ud explored the next steps to coordinate advocacy,\ud public health, and research into a\ud cogent health policy framework for the\ud American NTDs. It also highlighted how\ud U.S.-funded global health research can serve\ud to combat these health disparities in the\ud United States, in addition to benefiting\ud communities abroad

Preliminary Clinical Evaluation of Short Fiber-Reinforced Composite Resin in Posterior Teeth: 12-Months Report

This preliminary clinical trial evaluated 12 month clinical performance of novel filling composite resin system which combines short fiber-reinforced composite resin and conventional particulate filler composite resin in high stress bearing applications. A total of 37 class I and II restorations (compound and complex type) were placed in 6 premolars and 31 molars. The restorations were reviewed clinically at 6 months (baseline) and 12 months using modified USPHS codes change criteria for marginal adaptation, post-operative sensitivity, pulpal pain and secondary caries criteria. Photographs and x-rays were obtained for restorative analysis. Results of 12 months evaluation showed 5 restorations having little marginal leakage (B score) and 1 patient had minor pulpal symptom and post-operative sensitivity (B score). No secondary caries or bulk fracture was detected. The majority of restorations exhibited A scores of the evaluated criteria. After 12 months, restorations combining base of short fiber reinforced composite resin as substructure and surface layer of hybrid composite resin displayed promising performance in high load bearing areas

Nut consumption and risk of atrial fibrillation in the Physicians' Health Study

<p>Abstract</p> <p>Background</p> <p>Atrial Fibrillation is highly prevalent in clinical practice affecting approximately 2.3 million people in USA and 4.5 million people in European Union. The aim of the study was to examine the association between nut consumption and incident atrial fibrillation.</p> <p>Methods</p> <p>Prospective cohort of 21,054 male participants of Physicians' Health Study I. Nut consumption was estimated using food frequency questionnaire and incident atrial fibrillation was ascertained through yearly follow-up questionnaires. Cox regression was used to estimate relative risks of atrial fibrillation.</p> <p>Results</p> <p>The average age was 54.6 ± 9.5 years (40.7-87.1). During a mean follow up of 20 years (median 24 years), 3,317 cases of atrial fibrillation occurred. The crude incidence rate was 7.6, 7.4, 8.2, 7.9, and 6.8 cases/1000 person-years for people reporting nut consumption of rarely/never, 1-3/month, 1/per week, 2-6/week, and ≥ 7/week, respectively. Multivariable adjusted hazard ratios (95% CI) for incident atrial fibrillation were 1.00 (ref), 1.00 (0.90-1.11), 1.09 (0.97-1.21), 1.07 (0.95-1.21), and 0.91 (0.70-1.17) for nut consumption from the lowest to the highest category of nut consumption (p for trend 0.26). No statistically significant association between nut consumption and atrial fibrillation was found when stratified by body mass index (BMI < 25 vs ≥ 25 kg/m²) or age (< 65 vs. ≥ 65 years).</p> <p>Conclusions</p> <p>Our data did not show an association between nut consumption and incident atrial fibrillation among US male physicians.</p